Platelets, once regarded simply as ”blood dust,” are now recognized to play essential roles in hemostasis. Not only do they form a hemostatic plug and initiate thrombus formation in the event of vascular injury, but they also repair minute vascular damage that occurs on a daily basis. Platelets also participate in wound healing and angiogenesis via the delivery of key growth factors to sites of vascular…
Granulocytopoiesis Granulocytes (neutrophils, eosinophils, and basophils) are short-lived cells that are critical to both antimicrobial and inflammatory responses. The bone marrow (BM) produces granulocytes, particularly neutrophils, at a prodigious rate to supply the baseline need for circulating cells that survive in the peripheral blood for only 3 to 24 hours. It also has the capacity to sharply increase granulocyte production in response to a wide range…
The production of erythroid cells is a dynamic and exquisitely regulated process. The mature red cell is the final phase of a complex but orderly series of genetic events that is initiated when a multipotent stem cell commits to the erythroid program. Expression of the erythroid program occurs several divisions later in a greatly amplified population of erythroid cells, which have a characteristic form and structure,…
Conventional modalities for treating cancer remain unsatisfactory. Despite the introduction of small molecules that target specific molecular lesions or pathways within the cancer cells, cure rates for many common tumors remain low, while adverse events are still distressingly high. Cancer immunotherapy represents a promising extension of highly targeted cAncer therapy with potentially favorable toxicity and pharmacoeconomic profiles. Until recently, most attention has been on the development…
T lymphocytes have the natural ability to destroy viral-infected or tumor target cells by a range of mechanisms that are initiated upon recognition of target peptides presented by histocompatibility antigens. Coupled with their ability to traffic through multiple tissues and self-renew, these properties make T lymphocytes an appealing cell-type for adoptive immunotherapy of cancer. Allogeneic hematopoietic stem cell transplantation (HSCT) is enduring “proof-of-principle” for adoptive immunotherapy…
Thymus-derived lymphocytes (T cells) play an essential role in the immune response to pathogens and against host cells that have undergone malignant transformation. T cells are critical regulators of the immune system that act through production of soluble mediators and direct interactions between ligands on the T-cell surface and receptors on other immune cells. This chapter reviews T-cell activation after engagement with specific antigens and describes…
Complement and immunoglobulins represent the two major arms of humoral immunity and are discussed in detail in respective major subsections of this chapter. The complement section begins with a comprehensive overview of pathway activation, regulation, and effector mechanisms, followed by discussion of the pathological consequences of various complement deficiencies and polymorphisms. Next discussed is complement’s integral role in B-cell and T-cell immunity. Additional topics include the…
B lymphocytes are the subset of white blood cells specialized to synthesize and secrete immunoglobulin (Ig). Their name derives from the finding that the avian b ursa of Fabricius is a site of B-cell production. However, post-natal B-cell production in mammals takes place in the bone marrow. Following their production, newly generated B lymphocytes migrate into secondary lymphoid organs such as the spleen where they undergo…
Natural killer (NK) cells are large, granular lymphocytes that comprise about 10% to 15% of the circulating peripheral blood lymphoctyes. These unique cells were first characterized by their ability to lyse targets independently of activating or initiating stimuli. NK cells are a critical cellular component of the innate immune system that have the ability to target and lyse malignant and virally infected cells. In addition, NK…
Dendritic cells (DCs), originally discovered in 1973 by Ralph M. Steinman and Zanvil A. Cohn and named after their distinct stellate morphology, are important regulators of immune responses. Specialized in antigen acquisition, processing, and presentation, the hallmark of DCs is their ability to induce naïve T cell activation and effector differentiation. DCs also interact with other immune cells, such as B cells, natural killer (NK) cells,…
Aging Increase in life expectancy has resulted in a major demographic global shift toward an elderly population. As a consequence, the prevalence of a multitude of age-associated diseases has increased gradually during the last decades, resulting in an increased number of hospitalizations of elderly individuals. A better understanding of the mechanisms that cause aging is crucial in order to mitigate age-associated clinical conditions. Multiple “hallmarks” of…
Core Apoptosis Pathways Apoptosis is a biochemically well-defined programmed cell death that is essential for normal development and cellular homeostasis; dysregulation of apoptosis is involved in several diseases. The classical morphological features of apoptosis include cell shrinkage, membrane blebbing, nuclear condensation, and deoxyribonucleic acid (DNA) fragmentation. The biochemical hallmarks of apoptosis include permeabilization of the outer mitochondrial membrane (MOMP), activation of caspases, and the externalization of…
The Cell Division Cycle The mammalian cell cycle is divided into four phases: mitosis (M), deoxyribonucleic acid (DNA) synthesis (S), and the gap phases G1 and G2 ( Fig. 17.1 ). Mitosis is recognized when cells visibly undergo cell division and chromatin becomes condensed, sequentially progressing through prophase, metaphase, anaphase, and telophase. The G1 phase occurs immediately after mitosis has been completed and ends when DNA…
Introduction Hallmarks of hematopoietic stem and progenitor cell (HSPC) function include their dynamic metabolism, active bi-directional migration (bone marrow [BM] homing, egress, recruitment, and mobilization to the blood), durable multilineage BM and blood repopulation potential, self-renewal and chemotherapy resistance. Hematopoietic stem cells (HSCs) mainly reside in the BM, and their chemotherapy resistance requires their quiescence, adhesion, and metabolic interactions with bone-forming stromal cells. However, HSPCs are…
Cell adhesion is essential for the development and maintenance of multicellular organisms. Cell-to-cell and cell-to-matrix adhesion provide a mechanism for intercellular communication and to define the three-dimensional architecture of organs. The regulated nature of cell adhesion is particularly evident in the hematopoietic system, where blood cells routinely make transitions between nonadherent and adherent phenotypes during differentiation, and in response to stimuli in the circulation or extravascular…
Evolution of the Niche Concept In 1868, Ernest Neumann first suggested that blood cells are being replenished throughout postnatal life, and this proposal led to the attempts to localize the place of hematopoiesis. His hypothesis that blood cell production takes place in the bone marrow (BM) was experimentally validated by selective lead shielding of limbs in irradiated animals almost a century later. Notably, these and other…
Cell-Of-Origin Studies in Hematologic Malignancies One of the prevailing models of cancer development proposes that a cancer is initiated and maintained through the function of CSCs, which represent a rare population of cells within a cancer that have an indefinite proliferative potential and are ultimately responsible for the generation of the bulk of cancer cells. This so-called CSC hypothesis has been best studied in hematopoietic malignancies.…
The mammalian immune system has evolved to mount multifaceted molecular and cellular microbicidal responses tailored and custom-adapted to eliminate an endless variety of infectious agents and, at the same time, remain tolerant to self-antigens. Accomplishing these tasks requires continuous tightly controlled movement of billions of motile immune cells that roam throughout the body along distinct nonrandom traffic routes from one tissue to another using blood and…
Introduction Hematopoiesis is regulated by cytokine-cell and cell-cell interactions. Cytokines are polypeptides secreted by many cell types either constitutively or after induction and are usually classified based on primary structures associated with their receptor extracellular domains. They regulate a large range of biologic functions, including hematopoiesis, immunity, and inflammation. In context of hematopoiesis, they have effects on proliferation, differentiation, survival/cell death (apoptosis), and cell movement/migration/induced mobilization.…
Mitochondrial Structure and Function Mitochondria are very complex and highly dynamic organelles. Although responsible for only 10% of the cellular proteome, mitochondria serve not only as powerhouse of the cells but also as critical regulators of essential cellular processes including iron-sulfur cluster biosynthesis, calcium homeostasis, and cell death; hence they contribute to health and disease. Mitochondria are surrounded by a double-membrane system, consisting of an inner…